Page 7 of 9
Organic Process Research & Development
L) and then subjected to atmospheric distillation to re-
that the reaction temperature remained between 25 °C
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and 35 °C. After the addition of triethylamine was com-
plete, the reaction mixture was heated to about 55 °C and
stirred at that temperature until complete by HPLC (reac-
tion was deemed complete when <1.5% 32 was seen). The
reaction was cooled to about 20 °C, treated with water
move the THF solvent. Once the distillation was com-
plete, the solution temperature was adjusted with stirring
to 70 °C. The solution temperature was then slowly de-
creased with stirring from 70 °C to 50 °C at a rate of 0.1 °C
per minute and then from 50 °C to 0-5 °C at a rate of
0.25 °C per minute. The resulting slurry was filtered; the
wet cake was dried in a vacuum oven at 65 °C to afford
(
279 L), and the mixture was stirred for 2 h. The resulting
solids were filtered and the wet cake was washed with
water (2 X 69.8 L). The wet cake 33 was charged into a
vessel and dissolved in THF (399.0 L). Solid L-cysteine
50.4 kg (110.4 mol; 92.5% yield) of 1 as a white colored
1
solid. H NMR (400 MHz, DMSO-d ) δ 8.44 (d, J = 3.0 Hz,
6
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(
(
8.09 kg) (a palladium scavenger) was dissolved in water
198.1 L) and added to the 33 solution. The resulting mix-
1H), 8.28 (d, J = 8.8 Hz, 2H), 8.06 (d, J = 8.8 Hz, 1H), 7.99
(bd, J = 8.5 Hz, 2H), 7.54 (dd, J = 8.8, 3.0 Hz, 1H), 4.03 (d,
J=6.3 Hz, 2H), 4.03-3.97 (m, 2H), 3.25 (s, 3H), 3.20-3.09
(m, 2H), 2.81 (q, J = 6.7 Hz, 1H), 2.13-2.00 (m, 1H), 1.88 (bd,
J = 12.8 H, 2H), 1.42-1.29 (m, 2H), 1.18 (d, J = 7.0 Hz, 6H).
ture was stirred at about 60 °C for 1 h. The reaction mix-
ture was filtered and transferred to a clean vessel. The
layers were allowed to settle and separate. The aqueous
bottom layer was separated and transferred to a vessel
and back-extracted with DCM (139.5 L). The biphasic
solution was stirred for 15 min; the stirring was halted and
the layers were allowed to separate. The DCM-based or-
ganic layer, after filtration, was combined with the first
THF-base organic layer with stirring. After the stirring
was halted and the layers separated, the aqueous layer
was discarded. The DCM/THF based organic layer con-
taining 33 was then distilled down to about 279 L. Etha-
nol (390.6 L) was added and the solution was concentrat-
ed to about 279 L. The temperature of the ethanol solu-
tion was adjusted to about 55 °C and then slowly cooled
to about 0 °C at a rate of 0.5 °C/min. The resulting slurry
was then stirred for at least 2 hours at 0 °C. The slurry
was then filtered. The wet cake was washed with cold
EtOH (2 X 139.5 L). The wet cake was dried under vacuum
at about 50 °C to afford 35.8 kg (142.5 mol; 89.9% yield) of
1
3
C NMR (100.6 MHz, DMSO-d ) 175.3, 170.9, 155.5, 147.0,
6
143.5, 140.5, 138.6, 127.9, 127.0, 122.4, 122.3, 72.5, 45.7, 44.1,
35.0, 28.0, 26.7, 20.8. HRMS calcd for C H N O S (M +
2
3
29
4
4
+
H) 457.1904, found, 457.1900.
Anal. Calcd for
C H N O S: C, 60.51; H, 6.18; N, 12.27. Found: C, 60.64;
23
28
4
4
H, 6.16; N, 12.24.
Preparation of API grade GSK1292263A (1)
In a nitrogen purged vessel, a stirring suspension of 1
(
30.0 kg, 65.71 mol) in 2-methyl tetrahydrofuran (630 L )
initially at ambient temperature was heated to 70-80 °C.
The resulting homogeneous solution was transferred
through an appropriate in-line filter containing activated
carbon (Darco G-60, 5.01 kg) sandwiched between two
layers of filtering agent (Celite 545, 2 X 20.1 kg into a se-
cond nitrogen purged and pre-heated reactor vessel. The
filterpad was rinsed with additional methyl tetrahydrofu-
ran (60 L) and the filtered solution was concentrated in
vacuo to about 510 L. The concentrate was reheated to 70-
1
33 as a white colored solid. H NMR (400 MHz, DMSO-
d6) δ 8.73 (d, J = 2.8 Hz, 1H), 8.31 (bd, J = 8.8 Hz, 2H), 8.20
(dd, J = 8.8, 4.3 Hz, 1H), 8.04 (bd, J = 8.5 Hz, 2H), 7.91 (td,
1
3
80 °C. Once complete dissolution was established, the
J = 8.8, 3.0 Hz, 1H), 3.27 (s, 3H). C (100.6 MHz, DMSO-
batch temperature was reduced to 55 °C over approxi-
mately 30 minutes and seeded with GSK1292263A (0.15
kg) suspended in a minimal amount of filtered 2-methyl
tetrahydrofuran (0.18 L) (0.006 vol.). The mixture was
then cooled to 35 °C at a rate of 0.1 °C/min and then
cooled to 0 °C at a rate of 0.25 °C/min. The resulting slur-
ry was then stirred at about 0 °C for 1 h. The product was
filtered. The wet cake was rinsed with pre-chilled 2-
methyl tetrahydrofuran (2 X 60 L). The material was
dried at 60-65 °C under vacuum to afford 22.51 kg (49.30
mol; 75.0% yield) of 1 as a white colored solid.
d6) 158.3, 151.3, 142.7, 141.3, 138.4, 128.0, 127.8, 125.0, 124.8,
+
123.3, 123.2, 44.0. HRMS calcd for C H FNO S (M + H)
1
2
11
2
252.0489, found, 252.0485.
Preparation of intermediate grade GSK1292263A (1)
Potassium t-butoxide (28.1 kg, 250.42 mol) and THF
148.4 L) were added to a vessel. The resulting slurry was
(
cooled to 0-5 °C. The vessel was then charged with a so-
lution of crude 7 (29.58 kg, 131.33 mol) dissolved in DMPU
(
59.2 L) at a rate such that the temperature remained be-
low 15 °C. The reaction mixture was stirred for 30
minutes at 0-5 °C. The vessel was treated with a solution
of 33 (30.0 kg, 119.39 mol) in THF (121.5 L) and DMPU
ASSOCIATED CONTENT
Supporting Information
(
29.6 L) at a rate such that the reaction temperature was
kept below 15 °C. Once the addition was complete, the
reaction was held for about 30 min at 0-5 °C and then
warmed to 18-22 °C for approx-imately one hour. The
reaction was quenched with an aqueous sodium sulphite
solution [60.0 kg (476.03 mol) of solid sodium sulphite
dissolved in 360 L of water]. The resulting biphasic solu-
tion was heated with stirring to about 45 °C and then al-
lowed to settle and separate at 45 °C. The layers were
separated. The organic layer was treated with water (150
The Supporting Information is available free of charge on the
ACS Publications website.
Full characterization data for all new compounds (PDF)
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